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Multicenter Study
. 2019 Apr;266(4):876-887.
doi: 10.1007/s00415-019-09209-z. Epub 2019 Feb 20.

The histopathological spectrum of malignant hyperthermia and rhabdomyolysis due to RYR1 mutations

G J Knuiman  1 , B Küsters  1 , L Eshuis  1 , M Snoeck  2 , M Lammens  3 , L Heytens  4 , W De Ridder  5   6   7 , J Baets  5   6   7 , R S Scalco  8 , R Quinlivan  8 , J Holton  8 , I Bodi  9 , E Wraige  9 , A Radunovic  10 , C von Landenberg  11 , J Reimann  11 , E-J Kamsteeg  12 , C Sewry  13 , H Jungbluth  9   14   15 , N C Voermans  16
Affiliations
Multicenter Study

The histopathological spectrum of malignant hyperthermia and rhabdomyolysis due to RYR1 mutations

G J Knuiman et al. J Neurol. 2019 Apr.

Abstract

Objective: The histopathological features of malignant hyperthermia (MH) and non-anaesthetic (mostly exertional) rhabdomyolysis (RM) due to RYR1 mutations have only been reported in a few cases.

Methods: We performed a retrospective multi-centre cohort study focussing on the histopathological features of patients with MH or RM due to RYR1 mutations (1987-2017). All muscle biopsies were reviewed by a neuromuscular pathologist. Additional morphometric and electron microscopic analysis were performed where possible.

Results: Through the six participating centres we identified 50 patients from 46 families, including patients with MH (n = 31) and RM (n = 19). Overall, the biopsy of 90% of patients showed one or more myopathic features including: increased fibre size variability (n = 44), increase in the number of fibres with internal nuclei (n = 30), and type I fibre predominance (n = 13). Abnormalities on oxidative staining, generally considered to be more specifically associated with RYR1-related congenital myopathies, were observed in 52%, and included unevenness (n = 24), central cores (n = 7) and multi-minicores (n = 3). Apart from oxidative staining abnormalities more frequently observed in MH patients, the histopathological spectrum was similar between the two groups. There was no correlation between the presence of cores and the occurrence of clinically detectable weakness or presence of (likely) pathogenic variants.

Conclusions: Patients with RYR1-related MH and RM exhibit a similar histopathological spectrum, ranging from mild myopathic changes to cores and other features typical of RYR1-related congenital myopathies. Suggestive histopathological features may support RYR1 involvement, also in cases where the in vitro contracture test is not informative.

Keywords: Histology.; Malignant hyperthermia (MH); Muscle biopsy; RYR1; Rhabdomyolysis; RyR1.

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Conflict of interest statement

Conflicts of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Ethical standards

All studies in this review have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Figures

Fig. 1
Fig. 1
Histopathological features—haematoxylin & eosin (H&E) and Oil red O stain: features on H&E (a–c) range from normal appearance (a Patient 7) to increased fibre size variability and an increase in internal nuclei (b Patient 6, and c Patient 4), many of them central (b). On Oil red O stain (d Patient 34), there is marked increase in intracellular lipid, probably related to the timing of the muscle biopsy in relation to the RM episode in the patient
Fig. 2
Fig. 2
Histopathological features—oxidative stains and electron microscopy: abnormalities on oxidative stains range from mild unevenness of staining (a Patient 7) to overt cores and fibre type disproportion on NADH-TR stain (c Patient 4). Ring fibres (arrow) (b Patient 15) were noted in some cases. On electron microscopy, unstructured central cores (arrow) (d Patient 35) were occasionally noted. Size bar = 10 µm
See this image and copyright information in PMC

References

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